We have continued to investigate the molecular events leading to the establishment of herpes simplex virus (HSV) latent infections in the nervous system of experimentally inoculated mice and are determining the possible role of herpes simplex virus in neoplastic transformation. Regions of homology between the terminal repetitions of the HSV genome and the genomes of mice and humans have been identified and we have determined the nucleotide sequence of the viral and cellular DNA involved in these homologies. One of these regions is localized in the terminus of the HSV genome and shows strong homology with mouse DNA sequence very similar to immunoglobulin heavy chain genes involved in class-switch recombination. Another region of homology was found between an intergenic region of the immediate-early genes of HSV that has transcriptional enhancer activity and the regulatory region of the c-Ha-rasl oncogene isolated from the T24 human bladder carcinoma cell line. Deletion of the regulatory region in the oncogene led to the loss of its transforming activity, but its replacement by the HSV enhancer sequences in recombinant plasmid chimeras fully restored the transformation capacity of the c-Ha-rasl oncogene. A recombinant vaccinia virus which expresses glycoprotein D of HSV-1 has been tested for its efficacy as a live vaccine to prevent primary infections with HSV. Mice vaccinated with the recombinant virus developed neutralizing antibodies against HSV-1 and the vaccine protected mice against a lethal intraperitoneal challenge with HSV-1. The recombinant virus also prevented the establishment of a latent HSV infection in many of the experimentally challenged mice.